Pediatr Pulmonol. 2021 Apr 1. doi: 10.1002/ppul.25398. Online ahead of print.

ABSTRACT

AIMS: Transfer from paediatric to adult services could lead to clinical deterioration; few studies have examined this. We sought to examine the clinical impact of a structured individualised transition and transfer process in patients with cystic fibrosis (CF).

METHODS: Medical records of all patients with CF in Western Australia who transferred from a paediatric centre (Perth Children's Hospital, Perth, Western Australia) to an adult CF centre (Sir Charles Gairdner Hospital, Perth, Western Australia) between 2008 -2012 were reviewed. Data were extracted for two years before and after transfer. The number of CF outpatient visits, inpatient days and home intravenous antibiotic therapy (HIVT) days were recorded at yearly intervals before and after transfer. Sputum culture results at transfer were collected. All respiratory function and anthropometric data over the 4 years were extracted.

RESULTS: Forty-two patients with CF were transferred between 2008-2012. Mean age at transfer was 18.9 years (range 17-22). Compared to one-year pre-transfer, the frequency of outpatient visits at one and two years post-transfer increased. After transfer, there was no change in BMI, HIVT days or inpatient days, and no acceleration in the expected decline in FEV1.

CONCLUSION: This study found that transfer from a paediatric to an adult CF centre using a structured, individualised transition and transfer process was not associated with accelerated clinical deterioration. This article is protected by copyright. All rights reserved.

PMID:33793092 | DOI:10.1002/ppul.25398

Monaldi Arch Chest Dis. 2021 Mar 11;91(2). doi: 10.4081/monaldi.2021.1501.

ABSTRACT

Pulmonary rehabilitation is a key component in cystic fibrosis care. This review summarizes the recent evidence in the area of pulmonary rehabilitation for cystic fibrosis in the form of questions and answers regarding interventions, indications, benefits and risks of pulmonary rehabilitation. Pulmonary rehabilitation includes airway clearance techniques, exercise training, education and behaviour change and can improve patients' exercise capacity, muscle strength, quality of life and nutritional status. Airway clearance techniques have beneficial effects for clearing mucous. Over the past years, evidence for the beneficial effects of exercise training on exercise capacity and overall lung health is growing. In cystic fibrosis, multiple factors result in reduced exercise capacity. All modalities of pulmonary rehabilitation should be offered to patients with cystic fibrosis, as the benefits in most cases outweigh the risks, though the optimal regimens need to be yet defined.

PMID:33792230 | DOI:10.4081/monaldi.2021.1501

Arch Microbiol. 2021 Mar 31. doi: 10.1007/s00203-021-02300-y. Online ahead of print.

ABSTRACT

A homeostatic balance exists between the resident microbiota in the oral cavity and the host. Perturbations of the oral microbiota under particular conditions can contribute to the growth of non-oral pathogens that are hard to kill because of their higher resistance to antimicrobials, raising the probability of treatment failure and reinfection. The presence of these bacteria in the oral cavity has been proven to be associated with several oral diseases such as periodontitis, caries, and gingivitis, and systemic diseases of importance in clinical medicine such as cystic fibrosis, HIV, and rheumatoid arthritis. However, it is still controversial whether these species are merely transient members or unique to the oral cavity. Mutualistic and antagonistic interactions between the oral microbiota and non-oral pathogens can also occur, though the mechanisms used by these bacteria are not clear. Therefore, this review presents an overview of the current knowledge about the presence of non-oral bacteria in the oral cavity, their relationship with systemic and oral diseases, and their interactions with oral bacteria.

PMID:33791834 | DOI:10.1007/s00203-021-02300-y

Future Healthc J. 2021 Mar;8(1):e47-e49. doi: 10.7861/fhj.2020-0205.

ABSTRACT

People with cystic fibrosis (CF) were advised to undertake 'shielding' at home during the COVID-19 pandemic to reduce their risk of infection. We studied the impact shielding had on their wellbeing, mental health (GAD-7 and PHQ-9 scores) and adherence to treatment. 63 (46%) of 137 people surveyed responded (19 anonymously; 44 gave their identity). Most (94%) adhered to shielding advice 'all the time/often' but many (76%) found this difficult with disruption of their routines, relationships and exercise habits. Treatment adherence rates were high and continued during COVID-19. Depression scores were low and remained stable. Clinically significant anxiety rates rose from 27% pre-COVID-19 to 54% during COVID-19 and seven patients requested a psychology consultation from this study. There is a need to monitor the wellbeing of people with CF during the ongoing COVID-19 pandemic.

PMID:33791475 | PMC:PMC8004337 | DOI:10.7861/fhj.2020-0205

Infect Drug Resist. 2021 Mar 22;14:1141-1153. doi: 10.2147/IDR.S267219. eCollection 2021.

ABSTRACT

Cystic Fibrosis (CF) is an autosomal recessive disease characterized by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Impairment of the CFTR protein in the respiratory tract results in the formation of thick mucus, development of inflammation, destruction of bronchial tissue, and development of bacterial or fungal infections over time. CF patients are commonly colonized and/or infected with fungal organisms, Candida albicans or Aspergillus fumigatus, with prevalence rates ranging from 5% to 78% in the literature. Risk factors for acquiring fungal organisms include older age, coinfection with Pseudomonas aeruginosa, prolonged use of oral and inhaled antibiotics, and lower forced expiratory volume (FEV1). There are limited data available to differentiate between contamination, colonization, and active infection. Furthermore, the pathogenicity of colonization is variable in the literature as some studies report a decline in lung function associated with fungal colonization whereas others showed no difference. Limited data are available for the eradication of fungal colonization and the treatment of active invasive aspergillosis in adult CF patients. In this review article, we discuss the challenges in clinical practice and current literature available for laboratory findings, clinical diagnosis, and treatment options for fungal infections in adult CF patients.

PMID:33790585 | PMC:PMC7998013 | DOI:10.2147/IDR.S267219

Sci Transl Med. 2021 Mar 31;13(587):eabd8109. doi: 10.1126/scitranslmed.abd8109.

ABSTRACT

The concentration of chloride in sweat remains the most robust biomarker for confirmatory diagnosis of cystic fibrosis (CF), a common life-shortening genetic disorder. Early diagnosis via quantitative assessment of sweat chloride allows prompt initiation of care and is critically important to extend life expectancy and improve quality of life. The collection and analysis of sweat using conventional wrist-strapped devices and iontophoresis can be cumbersome, particularly for infants with fragile skin, who often have insufficient sweat production. Here, we introduce a soft, epidermal microfluidic device ("sweat sticker") designed for the simple and rapid collection and analysis of sweat. Intimate, conformal coupling with the skin supports nearly perfect efficiency in sweat collection without leakage. Real-time image analysis of chloride reagents allows for quantitative assessment of chloride concentrations using a smartphone camera, without requiring extraction of sweat or external analysis. Clinical validation studies involving patients with CF and healthy subjects, across a spectrum of age groups, support clinical equivalence compared to existing device platforms in terms of accuracy and demonstrate meaningful reductions in rates of leakage. The wearable microfluidic technologies and smartphone-based analytics reported here establish the foundation for diagnosis of CF outside of clinical settings.

PMID:33790027 | DOI:10.1126/scitranslmed.abd8109

mSphere. 2021 Mar 31;6(2):e00228-21. doi: 10.1128/mSphere.00228-21.

ABSTRACT

Chelsie Armbruster studies catheter-associated urinary tract infection and the contribution of microbe-microbe interactions to infection progression and severity. In this mSphere of Influence article, she reflects on how two papers, A. E. Frick-Cheng, A. Sintsova, S. N. Smith, M. Krauthammer, et al., mBio 11:e01412-20, 2020, https://doi.org/10.1128/mBio.01412-20, and D. M. Cornforth, F. L. Diggle, J. A. Melvin, J. M. Bomberger, and M. Whiteley, mBio 11:e03042-19, 2020, https://doi.org/10.1128/mBio.03042-19, have impacted her thinking about the bacterial strains and experimental models used to study pathogenesis.

PMID:33789942 | DOI:10.1128/mSphere.00228-21

J Pediatr Surg. 2021 Feb 24:S0022-3468(21)00181-0. doi: 10.1016/j.jpedsurg.2021.02.047. Online ahead of print.

ABSTRACT

BACKGROUND: Contemporary early outcome data of meconium Ileus (MI) in cystic fibrosis (CF) are lacking on a population level. We describe these and explore factors associated with successful non-operative management.

METHODS: A prospective population-cohort study using an established surveillance system (BAPS-CASS) was conducted October 2012-September 2014. Live-born infants with bowel-obstruction from inspissated meconium in the terminal ileum and CF were reported. Data are described as median (interquartile range, IQR).

RESULTS: 56 infants were identified. 14/56(25%) had primary laparotomy (13/23 complicated MI, 1/33 simple), the remainder underwent contrast enema. Twelve, (12/33 (36%) with simple MI) achieved decompression. 8/12 (67%) who decompressed had >1 enema vs 3/20 (15%) with simple MI who had laparotomy after enema. The number of enemas per infant (1-4), contrast agents and their concentration, were highly variable. Enterostomy was formed at 24/44(55%) of laparotomies. In infants with simple MI, time to full enteral feeds was 6 (2-10) days in those decompressing with enema vs 15 (9-19) days with laparotomy after enema. Case fatality was 4% (95% CI 0.4-12%). Two infants, both preterm died, both in the second month after birth.

CONCLUSIONS: Infants with simple MI achieving successful enema decompression were more likely to have had repeat enemas than those who proceeded to laparotomy. Successful non-operative management was associated with a shorter time to full feeds. The early management of infants with MI is highly variable and not standardised across the UK and Ireland.

PMID:33789802 | DOI:10.1016/j.jpedsurg.2021.02.047

BMC Pediatr. 2021 Mar 31;21(1):154. doi: 10.1186/s12887-021-02609-z.

ABSTRACT

BACKGROUND: Cystic Fibrosis (CF) is one of the most prevalent autosomal recessive inherited disease in Caucasians. Rates of CF were thought to be negligible in non-Caucasians but growing epidemiological evidence shows CF is more common in Indian, African, Hispanic, Asian, and other ethnic groups than previously thought. Almost all second-tier molecular diagnostic tools currently used to confirm the diagnosis of CF consist of panels of the most common CF-causing DNA variants in Caucasians. However non-Caucasian individuals with CF often have a different spectrum of pathogenic variants than Caucasians, limiting the clinical utility of existing molecular diagnostic panels in this group. As a consequence of racially inequitable CF testing frameworks, non-Caucasians with CF encounter greater delays in diagnosis and associated harms than Caucasians. An unbiased approach of detecting CF-causing DNA variants using full gene sequencing could potentially address racial inequality in current CF testing.

CASE PRESENTATION: We present the case of a female baby from rural India who had a borderline first-tier newborn screening result for CF. Instead of choosing a targeted CF panel for second-tier testing, we used next-generation DNA sequencing to comprehensively analyze the cystic fibrosis transmembrane conductance regulator gene as an unbiased approach for molecular confirmation of CF. Sequencing identified two pathogenic variants that cause CF. One variant (c.1521_1523delCTT) is the most common cause of CF, while the other variant (c.870-1G > C) is absent from all population allele databases and has not been found in the Indian population previously. The rare variant would not have been detected by all currently available targeted CF panels used for second- or third-tier molecular CF testing.

CONCLUSIONS: Our use of full gene sequencing as a second-tier CF test in a non-Caucasian patient avoided the problems of missed diagnosis from using Caucasian-biased targeted CF panels currently recommended for second-tier testing. Full gene sequencing should be considered as the standard methodology of second-tier CF testing to enable equal opportunity for CF diagnosis in non-Caucasians.

PMID:33789612 | DOI:10.1186/s12887-021-02609-z

Am J Respir Cell Mol Biol. 2021 Mar 31. doi: 10.1165/rcmb.2020-0349OC. Online ahead of print.

ABSTRACT

In a new born pig cystic fibrosis (CF) model, the ability of gland-containing airways to fight infection was affected by at least two major host-defense defects: impaired mucociliary transport and a lower airway-surface liquid (ASL) pH. In the gland-containing airways, ASL pH is balanced by CFTR and ATP12A, which respectively control HCO3- transport and proton secretion. We found that, although porcine small airway tissue expressed little ATP12A, the ASL of epithelial cultures from CF distal small airways (diameter <200 μm) were nevertheless more acidic (compared to non-CF). Therefore, we hypothesized that gland-containing airways vs. small airways control acidification using distinct mechanisms. Our microarray data suggested that small airway epithelia mediate proton secretion via ATP6V0D2, an isoform of the V0d subunit of the H+-translocating plasma membrane V-type ATPase. Immunofluorescence of small airways verified the expression of the V0d2 subunit isoform at the apical surface of Muc5B+ secretory cells, but not ciliated cells. Inhibiting the V-type ATPase with bafilomycin A1 elevated the ASL pH of small airway cultures, in the presence or absence of HCO3-, and decreased ASL viscosity. These data suggest that, unlike large airways, which are acidified by ATP12A activity, small airways are acidified by V-type ATPase, thus identifying V-type ATPase as a novel therapeutic target for small airways diseases.

PMID:33789071 | DOI:10.1165/rcmb.2020-0349OC

Am J Respir Cell Mol Biol. 2021 Mar 31. doi: 10.1165/rcmb.2021-0033LE. Online ahead of print.

NO ABSTRACT

PMID:33788673 | DOI:10.1165/rcmb.2021-0033LE

Am J Physiol Lung Cell Mol Physiol. 2021 Mar 31. doi: 10.1152/ajplung.00531.2020. Online ahead of print.

ABSTRACT

RATIONALE: The transient receptor potential vanilloid 1 (TRPV1) channel is expressed in human bronchial epithelium (HBE), where it transduces Ca2+ in response to airborne irritants. TRPV1 activation results in bronchoconstriction, cough, and mucus production, and may therefore contribute to the pathophysiology of obstructive airway disease. Since asthmatic children face the greatest risk of developing virus-induced airway obstruction, we hypothesized that changes in TRPV1 expression, localization, and functionin airway epithelium may play a role in bronchiolitis and asthma in childhood.

OBJECTIVES: We sought to measure TRPV1 protein expression, localization, and function in HBE cells from asthmatic vs. non-asthmatic children both at baseline and after RSV infection.

METHODS: We determined changes in TRPV1 protein expression, subcellular localization, and function both at baseline and after RSV infection in primary HBE cells from normal and asthmatic children.

RESULTS: Basal TRPV1 protein expression was higher in HBE from asthmatic vs. non-asthmatic children and primarily localized to plasma membranes (PM). During RSV infection, TRPV1 protein increased more in the PM of asthmatic HBE as compared to non-asthmatic cells. TRPV1-mediated increase in intracellular Ca2+ was greater in RSV-infected asthmatic cells, but this increase was attenuated when extracellular Ca2+ was removed. Nerve growth factor (NGF) recapitulated the effect of RSV on TRPV1 activation in HBE cells.

CONCLUSIONS: Our data suggest that asthmatic children have intrinsically hyperreactive airways due in part to higher TRPV1-mediated Ca2+ influx across epithelial membranes, and this abnormality is further exacerbated by NGF overexpression during RSV infection driving additional Ca2+ from intracellular stores.

PMID:33787326 | DOI:10.1152/ajplung.00531.2020

Cureus. 2021 Feb 24;13(2):e13526. doi: 10.7759/cureus.13526.

ABSTRACT

Cystic fibrosis (CF) is a progressive genetic disorder, inherited by the autosomal recessive mode of inheritance and more frequently seen in the Caucasian population with a carrier rate of 1:29 in Caucasian-Americans. Over 1800 cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations have been identified so far and the delta F 508 del mutation is the most common mutation. Gene sequencing and deletion/duplication analysis can detect mutations in 99% of people with a clinical diagnosis of CF. However, diagnostic testing can be challenging, as screening tests may be inconclusive and the routine gene mutation panel analysis may be negative due to some rare or undocumented mutations. We report a case of a two-year-old boy of Palestinian-Lebanese descent, with a history of raised immunoreactive trypsin test (IRT), positive sweat test, and phenotypical CF manifestations, found to have rare CF apparent homozygous CFTR (NM_000492.3) variant, c.3623del (p.Gly1208AlafsX3). In our case, genetic testing for 139 mutations done in Germany could not identify any defect. Only CFTR gene sequencing identified the above pathogenic variant. This reinforces the practice for a broad range of CFTR mutation analyses to detect ethnic-specific rare variants. This is the second case of this particular genetic mutation identified and the first to be reported in detail.

PMID:33786233 | PMC:PMC7994952 | DOI:10.7759/cureus.13526

Sci Rep. 2021 Mar 30;11(1):7154. doi: 10.1038/s41598-021-86491-w.

ABSTRACT

Pseudomonas aeruginosa (PA) is a leading cause of nosocomial infections and death in cystic fibrosis patients. The study was conducted to evaluate the physicochemical structure, biological activity and serum stability of a recombinant anti-PcrV single chain variable antibody fragment genetically attached to the mCH3cc domain. The stereochemical properties of scFv-mCH3 (YFL001) and scFv (YFL002) proteins as well as molecular interactions towards Pseudomonas aeruginosa PcrV were evaluated computationally. The subcloned fragments encoding YFL001 and YFL002 in pET28a were expressed within the E. coli BL21-DE3 strain. After Ni-NTA affinity chromatography, the biological activity of the proteins in inhibition of PA induced hemolysis as well as cellular cytotoxicity was assessed. In silico analysis revealed the satisfactory stereochemical quality of the models as well as common residues in their interface with PcrV. The structural differences of proteins through circular dichroism spectroscopy were confirmed by NMR analysis. Both proteins indicated inhibition of ExoU positive PA strains in hemolysis of red blood cells compared to ExoU negative strains as well as cytotoxicity effect on lung epithelial cells. The ELISA test showed the longer serum stability of the YFL001 molecule than YFL002. The results were encouraging to further evaluation of these two scFv molecules in animal models.

PMID:33785781 | DOI:10.1038/s41598-021-86491-w

mBio. 2021 Mar 30;12(2):e00047-21. doi: 10.1128/mBio.00047-21.

ABSTRACT

Pseudomonas aeruginosa and Staphylococcus aureus are two of the most common coinfecting bacteria in human infections, including the cystic fibrosis (CF) lung. There is emerging evidence that coinfection with these microbes enhances disease severity and antimicrobial tolerance through direct interactions. However, one of the challenges to studying microbial interactions relevant to human infection is the lack of experimental models with the versatility to investigate complex interaction dynamics while maintaining biological relevance. Here, we developed a model based on an in vitro medium that mimics human CF lung secretions (synthetic CF sputum medium [SCFM2]) and allows time-resolved assessment of fitness and community spatial structure at the micrometer scale. Our results reveal that P. aeruginosa and S. aureus coexist as spatially structured communities in SCFM2 under static growth conditions, with S. aureus enriched at a distance of 3.5 μm from P. aeruginosa Multispecies aggregates were rare, and aggregate (biofilm) sizes resembled those in human CF sputum. Elimination of P. aeruginosa's ability to produce the antistaphylococcal small molecule HQNO (2-heptyl-4-hydroxyquinoline N-oxide) had no effect on bacterial fitness but altered the spatial structure of the community by increasing the distance of S. aureus from P. aeruginosa to 7.6 μm. Lastly, we show that coculture with P. aeruginosa sensitizes S. aureus to killing by the antibiotic tobramycin compared to monoculture growth despite HQNO enhancing tolerance during coculture. Our findings reveal that SCFM2 is a powerful model for studying P. aeruginosa and S. aureus and that HQNO alters S. aureus biogeography and antibiotic susceptibility without affecting fitness.IMPORTANCE Many human infections result from the action of multispecies bacterial communities. Within these communities, bacteria have been proposed to directly interact via physical and chemical means, resulting in increased disease and antimicrobial tolerance. One of the challenges to studying multispecies infections is the lack of robust, infection-relevant model systems with the ability to study these interactions through time with micrometer-scale precision. Here, we developed a versatile in vitro model for studying the interactions between Pseudomonas aeruginosa and Staphylococcus aureus, two bacteria that commonly coexist in human infections. Using this model along with high-resolution, single-cell microscopy, we showed that P. aeruginosa and S. aureus form communities that are spatially structured at the micrometer scale, controlled in part by the production of an antimicrobial by P. aeruginosa In addition, we provide evidence that this antimicrobial enhances S. aureus tolerance to an aminoglycoside antibiotic only during coculture.

PMID:33785630 | DOI:10.1128/mBio.00047-21

mBio. 2021 Mar 30;12(2):e03431-20. doi: 10.1128/mBio.03431-20.

ABSTRACT

Mycobacterium abscessus is an opportunistic pathogen whose treatment is confounded by widespread multidrug resistance. The therapeutic use of bacteriophages against Mycobacterium abscessus infections offers a potential alternative approach, although the spectrum of phage susceptibilities among M. abscessus isolates is not known. We determined the phage infection profiles of 82 M. abscessus recent clinical isolates and find that colony morphotype-rough or smooth-is a key indicator of phage susceptibility. None of the smooth strains are efficiently killed by any phages, whereas 80% of rough strains are infected and efficiently killed by at least one phage. The repertoire of phages available for potential therapy of rough morphotype infections includes those with relatively broad host ranges, host range mutants of Mycobacterium smegmatis phages, and lytically propagated viruses derived from integrated prophages. The rough colony morphotype results from indels in the glycopeptidolipid synthesis genes mps1 and mps2, negating reversion to smooth as a common route to phage resistance. Resistance is thus rare, and although mutations in polyketide synthesis, uvrD2, and rpoZ can confer resistance, these likely also impair survival in vivo The expanded therapeutic repertoire and the resistance profiles show that small cocktails or single phages could be suitable for controlling infections with rough strains.IMPORTANCE Mycobacterium abscessus infections in cystic fibrosis patients are challenging to treat due to widespread antibiotic resistance. The therapeutic use of lytic bacteriophages presents a new potential strategy, but the great variation among clinical M. abscessus isolates demands determination of phage susceptibility prior to therapy. Elucidation of the variation in phage infection and factors determining it, expansion of the suite of therapeutic phage candidates, and a greater understanding of phage resistance mechanisms substantially advances the potential for broad implementation of new therapeutic options for M. abscessus infections.

PMID:33785625 | DOI:10.1128/mBio.03431-20

mBio. 2021 Mar 30;12(2):e03328-20. doi: 10.1128/mBio.03328-20.

ABSTRACT

The evolution of pathogens in response to selective pressures present during chronic infections can influence their persistence and virulence and the outcomes of antimicrobial therapy. Because subpopulations within an infection can be spatially separated and the host environment can fluctuate, an appreciation of the pathways under selection may be most easily revealed through the analysis of numerous isolates from single infections. Here, we continued our analysis of a set of clonally derived Clavispora (Candida) lusitaniae isolates from a single chronic lung infection with a striking enrichment in the number of alleles of MRR1 Genetic and genomic analyses found evidence for repeated acquisition of gain-of-function mutations that conferred constitutive Mrr1 activity. In the same population, there were multiple alleles with both gain-of-function mutations and secondary suppressor mutations that either attenuated or abolished the constitutive activity, suggesting the presence of counteracting selective pressures. Our studies demonstrated trade-offs between high Mrr1 activity, which confers resistance to the antifungal fluconazole, host factors, and bacterial products through its regulation of MDR1, and resistance to hydrogen peroxide, a reactive oxygen species produced in the neutrophilic environment associated with this infection. This inverse correlation between high Mrr1 activity and hydrogen peroxide resistance was observed in multiple Candida species and in serially collected populations from this individual over 3 years. These data lead us to propose that dynamic or variable selective pressures can be reflected in population genomics and that these dynamics can complicate the drug resistance profile of the population.IMPORTANCE Understanding microbial evolution within patients is critical for managing chronic infections and understanding host-pathogen interactions. Here, our analysis of multiple MRR1 alleles in isolates from a single Clavispora (Candida) lusitaniae infection revealed the selection for both high and low Mrr1 activity. Our studies reveal trade-offs between high Mrr1 activity, which confers resistance to the commonly used antifungal fluconazole, host antimicrobial peptides, and bacterial products, and resistance to hydrogen peroxide. This work suggests that spatial or temporal differences within chronic infections can support a large amount of dynamic and parallel evolution and that Mrr1 activity is under both positive and negative selective pressure to balance different traits that are important for microbial survival.

PMID:33785623 | DOI:10.1128/mBio.03328-20

Arch Dis Child. 2021 Mar 30:archdischild-2020-320680. doi: 10.1136/archdischild-2020-320680. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is the most common life-limiting inherited condition in Caucasians. It is a multisystem autosomal recessive disorder caused by variants in the gene for cystic fibrosis transmembrane conductance regulator (CFTR) protein, a cell-surface localised chloride channel that regulates absorption and secretion of salt and water across epithelia. Until recently, the treatment for CF was predicated on ameliorating and preventing the downstream symptoms of CFTR dysfunction, primarily recurrent respiratory infections and pancreatic exocrine failure. But a new class of therapy-the CFTR modulators, which treat the basic defect and decrease the complications of CF, leads to significantly improved pulmonary function, decreased respiratory infections and improved nutrition. The newest agent, a combination of elexacaftor, tezacaftor and ivacaftor, will be suitable for approximately 90% of all people with CF and is likely to decrease the morbidity and significantly increase the life expectancy for most people with CF. The major barrier to their widespread introduction has been their cost, with many countries unwilling or unable to fund them. Nevertheless, such is their therapeutic efficacy and their likely potent effect on life expectancy that their advent has wider societal implications for the care of children and adults with CF.

PMID:33785533 | DOI:10.1136/archdischild-2020-320680

Int J Antimicrob Agents. 2021 Mar 27:106328. doi: 10.1016/j.ijantimicag.2021.106328. Online ahead of print.

ABSTRACT

The global rise in nosocomial pneumonia caused by multidrug-resistant (MDR) Gram-negative pathogens and increasingly limited antibiotic treatment options are growing threats to modern medicine. As a result, older antibiotics like polymyxins are being used as drugs of last resort for MDR nosocomial pneumonia. Polymyxins are bactericidal against most aerobic Gram-negative bacilli, but the sub-therapeutic concentrations achieved at infection sites following high-dose intravenous administration make treatment challenging. Therefore, there is a need to consider alternate forms of polymyxin delivery to achieve the necessary concentrations at sites of infection. Several studies have evaluated the effectiveness of aerosolized polymyxins in patients with nosocomial pneumonia caused by MDR Gram-negative pathogens like Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Here we evaluate the pharmacokinetic data supporting the use of inhaled polymyxin in nosocomial pneumonia and provide insight into the limitations and challenges future studies should address. We have also reviewed the literature published between 2006 and 2020 on the use of aerosolized polymyxins for the treatment of nosocomial pneumonia including ventilator-associated pneumonia in patients without cystic fibrosis to evaluate their safety and efficacy as monotherapy or as adjuncts to intravenous antimicrobials. This review highlights the need for well-designed, multicenter studies with standardized methodologies to further evaluate the effectiveness of inhaled polymyxins and provide reliable PK/PD data to redefine appropriate dosing strategies.

PMID:33785362 | DOI:10.1016/j.ijantimicag.2021.106328

BMC Microbiol. 2021 Mar 30;21(1):96. doi: 10.1186/s12866-021-02159-5.

ABSTRACT

BACKGROUND: Azithromycin is commonly prescribed drug for individuals with cystic fibrosis (CF), with demonstrated benefits in reducing lung function decline, exacerbation occurrence and improving nutrition. As azithromycin has antimicrobial activity against components of the uncultured microbiome and increasingly the CF microbiome is implicated in disease pathogenesis - we postulated azithromycin may act through its manipulation. Herein we sought to determine if the CF microbiome changed following azithromycin use and if clinical benefit observed during azithromycin use associated with baseline community structure.

RESULTS: Drawing from a prospectively collected biobank we identified patients with sputum samples prior to, during and after initiating azithromycin and determined the composition of the CF microbial community by sequencing the V3-V4 region of the 16S rRNA gene. We categorized patients as responders if their rate of lung function decline improved after azithromycin initiation. Thirty-eight adults comprised our cohort, nine who had not utilized azithromycin in at least 3 years, and 29 who were completely naïve. We did not observe a major impact in the microbial community structure of CF sputum in the 2 years following azithromycin usage in either alpha or beta-diversity metrics. Seventeen patients (45%) were classified as Responders - demonstrating reduced lung function decline after azithromycin. Responders who were naïve to azithromycin had a modest clustering effect distinguishing them from those who were non-Responders, and had communities enriched with several organisms including Stenotrophomonas, but not Pseudomonas.

CONCLUSIONS: Azithromycin treatment did not associate with subsequent large changes in the CF microbiome structure. However, we found that baseline community structure associated with subsequent azithromycin response in CF adults.

PMID:33784986 | DOI:10.1186/s12866-021-02159-5